These laboratories have recently demonstrated participation of lysosomal elements in the coupled events linking specific steroid hormone capture and cyclic AMP elevation at the plasma membrane with selective metabolic activation of the cellular target. The data permit formation of a model predicting the function of lysosomes as an obligatory link in nucleocytoplasmic communication prior to genic activation in such cells. The sensitivity, specificity, selectivity, and rapid onset of the lysosomal response to sex steroids provide evidence for physiological significance of this phenomenon as a general mechanism for mediation of sequential secondary biochemical transformations in the hormone-stimulated target cell. From the parallels noted in the adrenal cortex following ACTH administration and in ovary exposed in vitro to LH, it now appears that these coupled responses are not limited to the action of steroid hormones and may have far broader implications in endocrine regulation. The present application proposes to analyze in depth the role of lysosomes in mediating the pleiotropic events which characterize stimulation of specific target cells by hormones, both steroid and peptidal. The studies will comprise analysis of biochemical and enzymatic profiles of selected target and control organs and their subcellular components, as influenced by endogenous and exogenous hormone levels. Special emphasis will be placed on ultra-rapid time course after hormonal exposure. Modification of these parameters by nonspecific environmental factors, such as drugs, UV- and X-irradiation and other selected physical and chemical agents known to influence the integrity of subcellular organelles, including lysosomes and mitochondria, will also be analyzed. Particular attention will be paid to the events culminating in genic activation. Detailed analyses of the potential for specific genic derepression will be undertaken of those nuclear fractions with acceptor functions for lysosomal acidic matricular proteins or which serve as substrates for lysosomal hydrolases. Complementary investigations will be carried out on the influence of naturally-occurring and synthetic lysosomal membrane-stabilizing substances in modification of hormone responsiveness. Thus, it appears that a novel and promising approach is presently available to numerous basic problems in the biology of hormone action.